Divergent clonal selection dominates medulloblastoma at recurrence.

A Sorana Morrissy, Livia Garzia, David J H Shih, Scott Zuyderduyn, Xi Huang, Patryk Skowron, Marc Remke, Florence M G Cavalli, Vijay Ramaswamy, Patricia E Lindsay, Salomeh Jelveh, Laura K Donovan, Xin Wang, Betty Luu, Kory Zayne, Yisu Li, Chelsea Mayoh, Nina Thiessen, Eloi Mercier, Karen L Mungall, Yusanne Ma, Kane Tse, Thomas Zeng, Karey Shumansky, Andrew J L Roth, Sohrab Shah, Hamza Farooq, Noriyuki Kijima, Borja L Holgado, John J Y Lee, Stuart Matan-Lithwick, Jessica Liu, Stephen C Mack, Alex Manno, K A Michealraj, Carolina Nor, John Peacock, Lei Qin, Juri Reimand, Adi Rolider, Yuan Y Thompson, Xiaochong Wu, Trevor Pugh, Adrian Ally, Mikhail Bilenky, Yaron S N Butterfield, Rebecca Carlsen, Young Cheng, Eric Chuah, Richard D Corbett, Noreen Dhalla, An He, Darlene Lee, Haiyan I Li, William Long, Michael Mayo, Patrick Plettner, Jenny Q Qian, Jacqueline E Schein, Angela Tam, Tina Wong, Inanc Birol, Yongjun Zhao, Claudia C Faria, José Pimentel, Sofia Nunes, Tarek Shalaby, Michael Grotzer, Ian F Pollack, Ronald L Hamilton, Xiao-Nan Li, Anne E Bendel, Daniel W Fults, Andrew W Walter, Toshihiro Kumabe, Teiji Tominaga, V Peter Collins, Yoon-Jae Cho, Caitlin Hoffman, David Lyden, Jeffrey H Wisoff, James H Garvin, Duncan S Stearns, Luca Massimi, Ulrich Schüller, Jaroslav Sterba, Karel Zitterbart, Stephanie Puget, Olivier Ayrault, Sandra E Dunn, Daniela P C Tirapelli, Carlos G Carlotti, Helen Wheeler, Andrew R Hallahan, Wendy Ingram, Tobey J MacDonald, Jeffrey J Olson, Erwin G Van Meir, Ji-Yeoun Lee, Kyu-Chang Wang, Seung-Ki Kim, Byung-Kyu Cho, Torsten Pietsch, Gudrun Fleischhack, Stephan Tippelt, Young Shin Ra, Simon Bailey, Janet C Lindsey, Steven C Clifford, Charles G Eberhart, Michael K Cooper, Roger J Packer, Maura Massimino, Maria Luisa Garre, Ute Bartels, Uri Tabori, Cynthia E Hawkins, Peter Dirks, Eric Bouffet, James T Rutka, Robert J Wechsler-Reya, William A Weiss, Lara S Collier, Adam J Dupuy, Andrey Korshunov, David T W Jones, Marcel Kool, Paul A Northcott, Stefan M Pfister, David A Largaespada, Andrew J Mungall, Richard A Moore, Nada Jabado, Gary D Bader, Steven J M Jones, David Malkin, Marco A Marra, Michael D Taylor, Nature 529, 351-7 (2016)
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Abstract

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.